Not applicable
A study in the mid-1980""s estimated that about four and a half million people suffer fractures each year in the United States alone. In adults, fractures of the radius and/or ulna of the forearm, and fibula or ankle bone are frequently treated by immobilizing the fracture by the surgical attachment of a metal plate adjacent the fracture. Similarly, in some adults and most children, fractures of the neck of the femur or hip are frequently treated by immobilizing the fracture with a metal plate. In addition to its use in treating fractures of the radius, ulna and femur, metal plate may also used to immobilize other bones in both the treatment of fractures and in corrective surgery. The metal plate, typically made of a titanium-based metal, a stainless-steel, or a cobalt-chromium metal, is attached to the bone by bone screws. It should be noted that although the immobilization device is referred to as a plate, its size and shape is dictated by the application in which it is to be used.
As the bone heals it is necessary to remove the metal plate by means of a second surgical intervention. The reason for this is that the presence of the metal plate adjacent the bone ultimately results in what is referred to as xe2x80x9cplate induced osteopeniaxe2x80x9d or loss of bone mass. The reasons for this loss of bone mass are not fully understood but appear to be related both to changes in bone stress and changes in bone blood flow. Such bone remodeling in children may lead to growth restriction, especially when plates are used in craniofacial or maxillofacial intervention to repair congenital deformities.
Thus, it is desirable to replace metallic surgical devices, e.g., plates, presently used in surgical procedures with a bioerodible polymer, i.e., one that will dissolve and be absorbed by the body as the underlying bone heals. With such a bioerodible device, the necessity of a second surgical operation and its concomitant trauma as well as the deleterious effects caused by the presence of a plate for a long period of time is removed. Furthermore, unlike metals, these devices do not corrode and the modulus of the material may be more closely matched to that of bone. Two polymers that have been used to form bioerodible surgical plates are polylactic acid (PLA) and copolymers of lactic and glycolic acids (PLGA).
The mechanism for bioeroding polymers of lactic acid and copolymers of lactic and glycolic acids is not completely understood. The polymers are probably hydrolyzed in situ to their respective monomers and the resulting monomers are excreted from the body in the urine or expired from the body as carbon dioxide without ill effect. The body""s tolerance of these monomers probably results from the fact that lactic acid and glycolic acid are present as natural substances within tissue.
Although polymers of, e.g., PLA degrade as desired, plates constructed of PLA have a tendency to warp or distort in bone applications and thereby fail to appropriately immobilize fractures with respect to bending movements. This bowing apparently occurs because the side of the plate immediately adjacent the bone is exposed to a different aqueous environment than the side of the plate adjacent soft tissue. As water is adsorbed into the polymer, the polymer swells. Thus the difference in the aqueous environment of the two surfaces of the plate causes a differential in the amount of water entering the plate through each surface. This differential water adsorption results in turn in the differential swelling of the two sides of the plate, with bowing therefore occurring. Thus, it is desirable to form a surgical plate from a bioerodible polymer which is dimensionally stable.
A related matter of interest in bone repair involves ensuring that the fractured bone ends are properly stabilized when set, and maintaining this stabilization during healing. A bioerodible bone cement could be used to bridge the area of excised bone fragments and thus aid in healing. Secondly, a bioerodible bone cement could additionally be used in conjunction with bone repair proteins (BRPs) to promote active bone growth, i.e., the bone cement could function as an osteoinductive material. Also, because the rate of infection following fracture repair surgery may be as high as 11%, it would also be desirable to incorporate various antibiotics into the bone cement for slow release at the surgical site to minimize infection. Ideally, therefore, such a bone cement or xe2x80x9cgroutxe2x80x9d should be moldable in the surgical setting, should set to form a strong solid, should stabilize at the implant site, and should support and aid the bone healing process. In conjunction with cement use or, in some cases, in place of a cement, a bioerodible internal fixation device (IFD) made of a similar material can beneficially be used to stabilize the fracture.
With the use of minimally invasive techniques, a bioresorbable and osteoconductive bone cement of low viscosity could be used by injecting the cement into the fracture site. This technique would help prevent complications such as repeated displacement, instability and malunion. The use of the cement may also warrant conservative treatment in patients with relative indications for operative management. These patients include older patients for whom mobility would be difficult in long leg casting, patients with irreducible fractures or a fracture which has slipped in a cast, patients with obese legs which limit the capability of casts to maintain reduction, and chronic alcohol abusers. In addition, patients with relative contraindications to operative treatment, such as vascular insufficiency, diabetes mellitus, soft tissue blisters, abrasions, contusions or burns, could be successfully managed in a conservative fashion, thus eliminating peri- and postoperative risk factors. Finally, patients with severe osteoporosis may benefit from the use of osteoconductive bone cement as an adjunct to conservative treatment. Aside from its use in the treatment of ankle and foot fractures, a bioresorbable and osteoconductive cement may be applicable for the treatment of undisplaced or minimally displaced lateral tibial plateau fractures that would normally warrant conservative treatment (depression less than 1 cm and valgus instability less than 10 degrees).
Other potential applications include use in spinal fusions, where autologous bone grafting is often necessary and allogeneic bone is used when autologous bone stocks are insufficient. In these cases, an osteoinductive bioresorbable bone cement could serve as a bone substitute.
Thus, a need exists for polymeric bioerodible materials which may be used in making bone cements that desirably have a wide range of precure viscosities (to allow injection of the cement to a bone site or which may be applied as a group) and that also desirably incorporate biologically active agents. Such bioerodible bone cements containing biologically active agents for release must be able to protect the agents from damage during curing and provide buffering capacity to obviate possible inflammatory foreign body response generated by bioerosion of the cement. Lastly, such polymeric bioerodible materials should also be useable to make IFDs having dimensional stability during the critical bone setting and healing period.
The invention is directed to bioerodible polymeric materials, and in particular to semi-interpenetrating network (xe2x80x9csemi-IPNxe2x80x9d) alloys that comprise a first bioerodible polymer capable of producing acidic products upon hydrolytic degradation; a second bioerodible polymer, which, preferably via crosslinking, provides a biopolymeric scaffolding or internal reinforcement; and optionally a buffering compound that buffers the acidic products within a desired pH range. In a preferred embodiment, the second bioerodible polymer comprises polypropylene fumarate (PPF) which is cross-linked, desirably by a vinyl monomer such as vinyl pyrrolidone (VP), to form the biopolymeric scaffolding which provides the semi-IPN with the requisite dimensional stability. A beneficial end use of this material is in the form of internal fixation devices (IFDs) such as bone supports, plates, and pins. Another beneficial end use is as cured bone cements for bone repair.
A bone cement system, for making such a cured bone cement, is also contemplated within the invention. For example, a multi-part bioerodible bone cement system of the invention capable of forming a bioerodible polymeric semi-IPN alloy, comprises a first bioerodible polymer (such as PLGA) capable of producing acidic products upon hydrolytic degradation; and a second bioerodible polymer (such as PPF), which provides a biopolymeric scaffolding or internal reinforcement, wherein the second bioerodible polymer is crosslinked in vivo to provide a hardened, semi-IPN alloy bone cement.
In another aspect, a bone cement system of the invention comprises a bioerodible scaffolding polymer (such as PPF), which when polymerized provides a hardened bone cement, the cement system further comprising a gas generating agent in stabilized form for providing the cured bone cement with pores for facilitating inward cell migration.
Both the bone cements and dimensionally stable IFDs of the invention may advantageously also contain other agents such as bone repair proteins (BRPs), bone morphogenic proteins (BMPs), bone scrapings from host bone, demineralized bone, bone chips and antibiotics, to, e.g., actively promote bone growth and prevent infection while the bone cement or IFD is in place. The biologically active agents are preferably within a protective polymer envelope. Furthermore, although the usual practice involving cements requires that they be allowed to cure in situ at the surgical site, a cement material may also be cured ex situ. Ex situ curing may be conducted in molds designed for particular applications or in stock shapes such as bars or rods, which may later be machined to any desired shape.